Project Summary The peptide hormone relaxin has traditionally been linked to the maternal adaptation of the cardiovascular system during the first trimester of pregnancy. By activating several molecular signaling events, relaxin has been proposed as a pleiotropic and cardioprotective hormone. Recent innovative studies by the PI and others have demonstrated that relaxin promotes vasodilatation and angiogenesis; ameliorates ischemia/reperfusion (I/R) injury, regulates extracellular matrix turnover and remodeling following acute myocardial infarction (AMI), suppresses arrhythmias post MI and reverses fibrosis. More recent studies from the PI?s laboratory demonstrated the infarct-sparing benefits of reperfusion therapy with relaxin against I/R injury as well as its role in suppressing the NLRP3 inflammasome. The purpose of this application is to investigate and characterize the role of relaxin receptor 1 (RXFP1) and a novel small molecule allosteric agonist (ML290) for prevention and treatment of ischemic cardiomyopathy and inflammasome-mediated adverse remodeling and heart failure. We will test the following hypotheses: 1) To investigate the protective effects of the small molecule ML290 on prevention of adverse remodeling post MI and mitigation of ischemic HF. We will study the impact of reperfusion therapy with ML290 on LV scar size, function and remodeling up to 8 weeks post MI. 2) To determine the chronic anti-inflammatory effect of RXFP1 signaling through suppression of NLRP3- inflammasome and the evolution of ischemic cardiomyopathy. 3) To study the impact of gain-of- function of cardiac RXFP1 following I/R injury and its role in attenuating adverse remodeling and progression to HF. These studies will be the first to demonstrate the protective effects of RXFP1 activation/overexpression for prevention of adverse remodeling following MI and also its potential therapeutic utility in the failing heart, possibly through attenuation of inflammasome-mediated maladaptive signaling. This is especially novel and the results will have a tremendous impact on further endorsing RXFP1 signaling as a potent therapeutic target for AMI and ischemic heart failure.